This is a new application designed to study ethnic, gender and hormonal status as factors in the response to acute cocaine intoxication. Specific attention will be paid to subjective reports of intoxication, Addiction Research Inventory scales, Profile of Mood State Scales, visual analog scales, instrumental joystick responding and reaction time performance. Frequent blood samples will be collected to quantify possible pharmacokinetic alterations in cocaine bioavailability. In addition, three of cocaine's metabolites (norcocaine, ecgonine methyl ester and benzoylecgonine) will be measured to determine if metabolic profiles are affected by the above factors. These data should help quantify the contribution of pharmacodynamic or pharmacokinetic factors in cocaine's response. Both the intranasal and intravenous cocaine will be studied to determine the importance of route of administration. The first experiment will measure ethnic factors by giving acute cocaine challenges to subjects belonging to the following groups: African American, Asian American, Caucasian and Latino. If no group differences are found, then the remainder of the studies will be conducted using a balanced proportion of subjects from these ethnic backgrounds. If significant differences in cocaine responses or kinetic profiles are found, then these findings will be incorporated into the design of the subsequent experiments and a scientific basis for not grouping subjects from various ethnic groups together will have been made. The second experiment will evaluate the degree to which various hormones play a role in an individuals response to cocaine. Embedded in this experiment is an assessment of gender differences to cocaine response and whether route of cocaine administration (intranasal or intravenous) is an important factor in the efficacy of these hormone treatments. We propose to study gonadotrophic hormones, spironolactone and thyroid hormone as they have proven to be the most effective agents in altering cocaine response in our pilot studies. Women will be studied during various phases of their menstrual cycle. The third experiment will evaluate whether women who take a combination of estrogen and progesterone (e.g., oral contraceptives) have different responses to cocaine. The fourth experiment will use the information gained in the prior experiments to select the most promising hormone to be tested in a cocaine self- administration study. After a training session, subjects will be given the opportunity to select between two different doses of cocaine or placebo in a controlled laboratory setting both with and without pretreatment medication. All behavioral, physiological and subjective report data will be collected as before and compared with the number of times cocaine is selected. These studies should reveal new and interesting data on the nature of the interactions among ethnic background, gender and hormonal status on cocaine response. This strategy represents a departure from the currently popular theme of studying pharmacotherapies that affect dopamine and/or serotonin systems. It is anticipated that information obtained in the present series of experiments will be useful in designing completely new strategies for treating cocaine abuse and dependence.